Abstract
cAMP response-element binding protein (CREB), a transcription factor involved in learning, memory and drug addiction, is phosphorylated by calcium-calmodulin-dependent protein kinase IV (CaMKIV). Here, we show that CaMKIV-knockout (KO) mice developed less analgesic tolerance after chronic morphine administration with no alteration in physical dependence or acute morphine-induced analgesia. The increase in phosphorylated CREB expression observed in wild-type mice after chronic morphine was absent in CaMKIV-KO mice, while there was no difference in the expression or phosphorylation of the micro-opioid receptor between groups. Morphine-treated CaMKIV-KO mice showed less G-protein uncoupling from the micro-opioid receptor than did wild-type mice, while uncoupling was similar in control wild-type and KO mice. In addition, morphine reduced inhibitory transmission to a greater degree in CaMKIV-KO mice than in controls after chronic morphine exposure. Our results provide novel evidence for the role of CaMKIV in the development of opioid analgesic tolerance but not physical dependence.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics, Opioid / administration & dosage*
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Animals
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Animals, Newborn
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Behavior, Animal
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Blotting, Western / methods
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases / deficiency
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Conditioning, Operant / drug effects
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Conditioning, Operant / physiology
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Cyclic AMP Response Element-Binding Protein / metabolism
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Dose-Response Relationship, Drug
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Drug Administration Schedule
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Drug Tolerance*
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
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Exploratory Behavior / physiology
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Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics
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Immunohistochemistry / methods
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Immunoprecipitation / methods
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In Vitro Techniques
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Potentials / radiation effects
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Morphine / administration & dosage*
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Neurons / drug effects
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Neurons / physiology
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Neurons / radiation effects
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Pain Measurement / methods
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Patch-Clamp Techniques / methods
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Radioligand Assay / methods
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Spinal Cord / cytology
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Sulfur Isotopes / pharmacokinetics
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Time Factors
Substances
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Analgesics, Opioid
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Cyclic AMP Response Element-Binding Protein
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Sulfur Isotopes
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Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
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Guanosine 5'-O-(3-Thiotriphosphate)
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Morphine
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases
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Camk4 protein, mouse